EP2289536A1 - Use of bone morphogenetic proteins for healing and repair of connective tissue attachment - Google Patents

Use of bone morphogenetic proteins for healing and repair of connective tissue attachment Download PDF

Info

Publication number
EP2289536A1
EP2289536A1 EP10179024A EP10179024A EP2289536A1 EP 2289536 A1 EP2289536 A1 EP 2289536A1 EP 10179024 A EP10179024 A EP 10179024A EP 10179024 A EP10179024 A EP 10179024A EP 2289536 A1 EP2289536 A1 EP 2289536A1
Authority
EP
European Patent Office
Prior art keywords
bone
bmp
tendon
connective tissue
tissue
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10179024A
Other languages
German (de)
English (en)
French (fr)
Inventor
John M. Wozney
Russel F. Warren
Scott A. Rodeo
Jo A. Hannafin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genetics Institute LLC
New York Society for Relief of Ruptured and Crippled
Original Assignee
Genetics Institute LLC
New York Society for Relief of Ruptured and Crippled
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23836637&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2289536(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Genetics Institute LLC, New York Society for Relief of Ruptured and Crippled filed Critical Genetics Institute LLC
Publication of EP2289536A1 publication Critical patent/EP2289536A1/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/10—Materials or treatment for tissue regeneration for reconstruction of tendons or ligaments

Definitions

  • the present invention relates to the field of tissue repair, specifically, the regeneration of a functional attachment between connective tissue, such as tendon, cartilage or ligament, to bone.
  • This functional attachment may be destroyed by trauma or stress, or by degenerative or congenital disease.
  • the present invention may be useful in reconstructive surgery or other procedures for the regeneration of a functional attachment between connective tissue and bone.
  • the present invention provides methods and compositions for regenerating a functional attachment between connective tissue and bone.
  • the present invention comprises methods of treating patients with detached or degenerated attachments of the tendon or ligament to bone.
  • Some examples include reconstructive surgery on the knee, shoulder, hand, ankle and elbow.
  • Particular areas where the present invention may prove useful include reconstruction of the anterior cruciate ligament (ACL), or the rotator cuff.
  • ACL anterior cruciate ligament
  • the methods and compositions of the present invention are advantageous in that they utilize osteogenic proteins, which may be produced via recombinant DNA technology, and therefore are of potentially unlimited supply.
  • the methods and compositions of the present invention are further advantageous in that regeneration of the attachment apparatus may be accelerated or may be of greater ultimate strength, and the attachment formed between connective tissue and bone may reach a functional strength sooner after surgery or repair is effected.
  • the methods and compositions of the present invention are further advantageous in that they induce the regeneration of the functional attachment between connective tissue and bone, while minimizing or avoiding formation of fibrous or granulation tissue at the interface between tissue types.
  • the methods of the present invention are particularly applicable to the fixation of a round tendon in a bone tunnel or a flat tendon onto a bone surface.
  • a common clinical example is reconstruction of the anterior cruciate ligament, (ACL). Reconstruction may be performed by using the central third of the patellar tendon with an attached bone block from both the tibia and patella, or by using the semitendinosus and gracilis tendons.
  • Benefits of the use of patellar tendon include immediate bony fixation allowing aggressive post-operative rehabilitation and increased strength.
  • the use of central third patellar tendon has been associated with adverse sequelae, including patellar fracture, patellar ligament rupture, and degeneration of the patellofemoral joint.
  • BMP tendon-to-bone healing
  • rhBMP-2 improves early healing of bone to a tendon graft, as demonstrated by histologic and biomechanical evaluation. Increased strength of tendon-to-bone fixation will allow earlier and more aggressive rehabilitation, resulting in earlier return to normal activities, work, or sport.
  • rotator cuff tendon repair to the greater tuberosity of the humerus
  • reattachment of the glenoid labrum to the scapular neck reconstruction of the lateral ankle ligaments using a tendon graft placed through bone tunnels
  • reconstruction of the medial collateral ligament of the elbow or knee using a tendon graft fixed to the surface of the bone or through bone tunnels reconstruction of the ulnar collateral ligament of the thumb using a tendon graft placed in a bone tunnel
  • repair of the flexor or extensor tendons of the digits into bone tunnels or to the surface of the bone of the phalanges repair of the flexor or extensor tendons of the digits into bone tunnels or to the surface of the bone of the phalanges.
  • the invention is broadly applicable to any situation in which connective tissue (tendon, ligament, labrum, fascia, or joint capsule) is reattached to bone, either to the surface of the bone or into a tunnel in the bone.
  • methods and compositions are provided for treatment of patients who require reconstructive surgery for repair of the functional attachment between connective tissue and bone.
  • the methods and composition are advantageous in that repair or improvement of the entire attachment apparatus may be effected: the tendon or ligament, the adjacent bone, as well as the functional attachment.
  • the methods comprise applying to the site in need of reconstructive surgery, or to the site of a defect, tear or detachment of connective tissue to bone, an amount of a composition comprising one or more purified osteogenic proteins which is effective to regenerate the functional attachment of the connective tissue to the bone.
  • the method may further comprise the administration of a composition comprising a purified or recombinant osteogenic protein to a site in need of regeneration of the connective tissue to bone attachment in a suitable carrier such that the connective tissue, the bone, and the functional attachment apparatus are regenerated, with reduced fibrous or granulation tissue at the site of attachment occurring.
  • the composition is preferably administered in combination with an effective carrier.
  • the osteogenic protein is preferably from the subclass of proteins known generally as bone morphogenetic proteins (BMPs), which have been disclosed to have osteogenic activity, and other growth and differentiation type activities.
  • BMPs include BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, and BMP-13, and may also include other members of the TGF- ⁇ superfamily of proteins, such as growth and differentiation factors, or GDFs, and MP52.
  • the structure of a number of GDFs are disclosed in WO 94/15965 , WO94/15949 WO95/01801 ; WO95/01802 ; WO94/21681 : WO94/1596
  • the structure of MP52 is disclosed in WO93/16099 .
  • the disclosures of the above applications are hereby incorporated by reference.
  • the BMP is preferably BMP-2, the sequence of which is disclosed in United States Patent 5,013,649 , the disclosure of which is hereby incorporated by reference.
  • Other BMPs known in the art can also be used. Presently, the most preferred BMP is BMP-2.
  • the BMP may be recombinantly produced, or purified from a protein composition.
  • the BMP may be homodimeric, or may be heterodimeric with other BMPs (e.g., a heterodimer composed of one monomer each of BMP-2 and BMP-6) or with other members of the TGF- ⁇ superfamily, such as activins, inhibins and TGF- ⁇ 1 (e.g., a heterodimer composed of one monomer each of a BMP and a related member of the TGF- ⁇ superfamily).
  • BMPs e.g., a heterodimer composed of one monomer each of BMP-2 and BMP-6
  • other members of the TGF- ⁇ superfamily such as activins, inhibins and TGF- ⁇ 1
  • TGF- ⁇ 1 e.g., a heterodimer composed of one monomer each of a BMP and a related member of the TGF- ⁇ superfamily
  • the amount of osteogenic protein useful herein is that amount effective to stimulate increased osteogenic activity of infiltrating progenitor cells, and will depend upon the size and nature of the defect being treated, as well as the carrier being employed. Generally, the amount of protein to be delivered is in a range of from about 0.05 to about 1.5 mg.
  • the osteogenic protein is administered together with an effective amount of a protein which is able to induce the formation of tendon- or ligament-like tissue.
  • a protein which is able to induce the formation of tendon- or ligament-like tissue.
  • proteins include BMP-12, BMP-13, and other members of the BMP-12 subfamily, as well as MP52. These proteins and their use for regeneration of tendon and ligament-like tissue are disclosed in United States application serial number serial number 08/362,670, filed on December 22, 1994 , the disclosure of which is hereby incorporated herein by reference.
  • a heterodimer in which one monomer unit is an osteogenic protein such as BMP-2, and the other monomer subunit is a tendon-inducing protein, such as BMP-12, is administered in accordance with the methods described below, in order to induce the formation of a functional attachment between connective tissue and bone.
  • Materials which may be useful as the carrier in practicing the present invention include pharmaceutically acceptable materials having viscosity and polarity such that, when added to the bone morphogenetic protein, form a composition that possesses appropriate handling characteristics (i.e., is neither too runny to remain at the defect site) for application to the site of reconstruction of the connective tissue to bone attachment.
  • Adding the carrier to the bone morphogenetic protein allows the protein to remain in the disease or lesion site for a time sufficient to allow the protein to increase the otherwise natural rate of regenerative osteogenic activity of the infiltrating mammalian progenitor cells, and to form a space in which new tissue can grow and allow for ingrowth of cells.
  • the carrier may also allow the bone morphogenetic protein to be released from the defect or lesion site over a time interval appropriate for optimally increasing the rate of regenerative osteogenic activity of the progenitor cells.
  • the most preferred family of carriers comprises collagenous materials.
  • Preferred collagen materials include Collastat R and Helistat R collagen sponges (Integra LifeSciences Corp., Plainsboro, N.J.). Other collagen materials which may be suitable for use in the present invention are described in United States Patents 5,206,028 ; United States Patent 5,024,841 ; United States Patent 5,256,418 .
  • the collagen carrier is preferably in the form of a sponge.
  • the collagen sponge may be loaded with protein prior to administration by soaking the sponge in the desired volume and concentration of protein for a suitable time period.
  • the collagen sponge is preferably soak loaded with protein in a range from about 10% to about 150% v/v [ml protein/cc dry sponge], more preferably about 10 to about 60% v/v.
  • the protein may be adsorbed to the collagen sponge during production.
  • bone morphogenetic protein is preferably added to the collagen sponge during production and lyophilized to form a unitary product.
  • the protein is preferably added in a ratio of from about 10 to about 150% v/v, more preferably in a range from about 60 to about 80% v/v.
  • Other forms of collagen which may be useful in the present invention are collagen gel, and cross-linked polymeric collagen.
  • porous particulate polymers are co-polymers of polylactic and polyglycolic acid.
  • the protein and polymers are preferably sequestered by a sequestering agent, such as autologous blood.
  • An alternative carrier useful for the present invention is a formulation of osteogenic protein, porous particulate polymers and another sequestering agent, such as cellulosic material.
  • sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol). Most preferred as the sequestering agent for this embodiment is carboxymethylcellulose. These compositions are described in published PCT application WO 93/00050 , the entire disclosure of which is hereby incorporated herein by reference.
  • the cellulosic protein sequestering agent is preferably present in a concentration of about 1 to about 10% (w/v implant).
  • the porous particulate polymer/cellulosic sequestering agent may optionally be further combined with aqueous glycerol as a diluent, preferably in concentrations of about 10 to about 80% (v/v); and ratios of sequestering agent/liquid solution:porous particulate polymers are preferably from about 0.1 to about 0.9 (v/v).
  • the porous particulate polymers may be formed into a fused sponge, as described in co-pending application serial number 08/308,787, filed on September 19, 1994 , the disclosure of which is hereby incorporated by reference.
  • the amount of osteogenic protein used with porous particulate polymers is generally in the range of .01 to 1 mg of protein, preferably .05 to .6 mg protein for each cubic centimeter of composition employed.
  • cellulosic materials such as alkylcellulose (including hydroxyalkylcellulose), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, the most preferred being the cationic salts of carboxymethylcellulose (CMC).
  • alkylcellulose including hydroxyalkylcellulose
  • CMC carboxymethylcellulose
  • the carrier be in the form of a hydrated cellulosic viscous gel. Viscosity may be increased through mechanical means, such as high agitation for a suitable period of time, followed by autoclaving, or chemically.
  • the BMP and cellulosic carrier is preferably in a solution of suitable buffer.
  • One preferred buffer solution is a composition comprising, in addition to the osteogenic protein, about 1.0 to about 10.0% (w/v) glycine, about 0.1 to about 5.0% (w/v) of a sugar, preferably sucrose, about 1 to about 20 mM glutamic acid hydrochloride, and optionally about 0.01 to about 0.1% of a non-ionic surfactant, such as polysorbate 80.
  • Preferred solutions are from about 1 % to about 20% w/v cellulosic carrier/buffer. If desired, a salt may be added.
  • a preferred viscous gel carrier is described in Example 2 below.
  • the amount of osteogenic protein useful with viscous gel carrier is generally in a range of from about 0.05 to about 1.5 mg, preferably from about 0.1 to about 1.0 mg per cubic centimeter of implant material required.
  • Other materials which may be suitable for use as carriers for BMPs in the methods and compositions of the present invention include hyaluronic acid, surgical mesh or sutures, polyglyconate, temperature-sensitive polymers, demineralized bone, minerals and ceramics, such as calcium phosphates, hydroxyapatite, etc., as well as combinations of the above described materials.
  • the protein of the present invention in a suitable buffer such as that described above, is applied directly to the site in need of tissue repair.
  • a suitable buffer such as that described above
  • the protein may be applied using a brush or other suitable applicator, such as a syringe for injection.
  • the protein may be directly applied to the site in need of tissue repair.
  • Example 1 BMP-2 and Collagen Sponge Polymer Carrier in Surgically Created Tendon to Bone Detachment Defects
  • the animals were anesthetized during surgery.
  • the knee joint was approached through a lateral parapatellar incision; the long digital extensor tendon was identified and then was detached from its insertion on the lateral femoral condyle by sharp dissection.
  • the fascia over the anterior tibialis muscle then was incised, and the muscle was retracted laterally.
  • Helistat R collagen sponge was loaded with recombinant human BMP-2 (rhBMP-2), and the sponge was then wrapped around the detached tendon.
  • the free end of the tendon was pulled manually through the drill-hole and was fixed, under tension, on the medial aspect of the proximal tibial metaphysis with simple interrupted sutures of 4-0 stainless steel.
  • the tendon fit snugly into the bone tunnel and was in contact with bone throughout the length of the tunnel.
  • the joint capsule, fascia, and subcutaneous tissues were closed with interrupted sutures of 3-0 chromic gut, and the skin was closed with interrupted sutures of 3-0 stainless steel.
  • the procedure then was done on the contralateral knee.
  • the limbs were not immobilized and the dogs were allowed exercise ad libitum in individual indoor runs.
  • rhBMP-2 induced extensive new bone deposition in this interface tissue, resulting in closer apposition of bone to the tendon at earlier time points and more regular establishment of Sharpey's fibers between the tendon and the bone in the rhBMP-2-treated limbs.
  • the increased strength of fixation correlates with the histologic degree of bone ingrowth seen in the rhBMP-2 treated limbs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Prostheses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Dental Preparations (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
EP10179024A 1995-06-05 1996-05-21 Use of bone morphogenetic proteins for healing and repair of connective tissue attachment Withdrawn EP2289536A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US46249795A 1995-06-05 1995-06-05
EP96916513A EP0831884B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenic proteins for healing and repair of connective tissue attachment
EP03015894.3A EP1364656B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenetic proteins for healing and repair of connective tissue attachment

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP96916513.3 Division 1996-12-12
EP03015894.3 Division 2003-07-11

Publications (1)

Publication Number Publication Date
EP2289536A1 true EP2289536A1 (en) 2011-03-02

Family

ID=23836637

Family Applications (3)

Application Number Title Priority Date Filing Date
EP10179024A Withdrawn EP2289536A1 (en) 1995-06-05 1996-05-21 Use of bone morphogenetic proteins for healing and repair of connective tissue attachment
EP96916513A Revoked EP0831884B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenic proteins for healing and repair of connective tissue attachment
EP03015894.3A Expired - Lifetime EP1364656B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenetic proteins for healing and repair of connective tissue attachment

Family Applications After (2)

Application Number Title Priority Date Filing Date
EP96916513A Revoked EP0831884B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenic proteins for healing and repair of connective tissue attachment
EP03015894.3A Expired - Lifetime EP1364656B1 (en) 1995-06-05 1996-05-21 Use of bone morphogenetic proteins for healing and repair of connective tissue attachment

Country Status (17)

Country Link
US (1) US6187742B1 (enExample)
EP (3) EP2289536A1 (enExample)
JP (1) JPH11507032A (enExample)
KR (1) KR100440645B1 (enExample)
CN (1) CN1133462C (enExample)
AT (1) ATE245996T1 (enExample)
AU (1) AU699918B2 (enExample)
CA (1) CA2220555C (enExample)
DE (1) DE69629294T2 (enExample)
DK (2) DK0831884T3 (enExample)
ES (2) ES2440441T3 (enExample)
FI (1) FI116511B (enExample)
HU (1) HU222664B1 (enExample)
OA (1) OA10547A (enExample)
PT (1) PT831884E (enExample)
TW (1) TW449478B (enExample)
WO (1) WO1996039169A1 (enExample)

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150328A (en) 1986-07-01 2000-11-21 Genetics Institute, Inc. BMP products
JP3504263B2 (ja) * 1991-11-04 2004-03-08 ジェネティックス・インスチチュート・リミテッド・ライアビリティ・カンパニー 組み換え型骨形態形成蛋白ヘテロダイマー、組成物および使用法
US20080070842A1 (en) * 1991-11-04 2008-03-20 David Israel Recombinant bone morphogenetic protein heterodimers, compositions and methods of use
US6291206B1 (en) 1993-09-17 2001-09-18 Genetics Institute, Inc. BMP receptor proteins
JP3717930B2 (ja) 1993-12-07 2005-11-16 ジェネティックス・インスチチュート・リミテッド・ライアビリティ・カンパニー Ｂｍｐ−１２、ｂｍｐ−１３およびそれらの腱誘導組成物
US5906827A (en) * 1994-06-03 1999-05-25 Creative Biomolecules, Inc. Matrix for the manufacture of autogenous replacement body parts
US6083522A (en) * 1997-01-09 2000-07-04 Neucoll, Inc. Devices for tissue repair and methods for preparation and use thereof
EP1350525A3 (en) † 1997-02-07 2003-12-10 Stryker Corporation Matrix-free osteogenic devices, implants and methods thereof
US20010016646A1 (en) 1998-03-20 2001-08-23 David C. Rueger Osteogenic devices and methods of use thereof for repair of endochondral bone, osteochondral and chondral defects
US7041641B2 (en) 1997-03-20 2006-05-09 Stryker Corporation Osteogenic devices and methods of use thereof for repair of endochondral bone and osteochondral defects
CN1068793C (zh) * 1997-04-17 2001-07-25 中国人民解放军第四军医大学全军创伤骨科研究所 骨生长刺激素注射剂及其制备方法
EP0896825B1 (en) 1997-08-14 2002-07-17 Sulzer Innotec Ag Composition and device for in vivo cartilage repair comprising nanocapsules with osteoinductive and/or chondroinductive factors
US6727224B1 (en) 1999-02-01 2004-04-27 Genetics Institute, Llc. Methods and compositions for healing and repair of articular cartilage
CA2386408A1 (en) 1999-10-15 2001-04-26 Genetics Institute, Inc. Formulations of hyaluronic acid for delivery of osteogenic proteins
US6626945B2 (en) 2000-03-14 2003-09-30 Chondrosite, Llc Cartilage repair plug
US6632246B1 (en) 2000-03-14 2003-10-14 Chondrosite, Llc Cartilage repair plug
US20020015734A1 (en) * 2000-03-23 2002-02-07 Genetics Institute, Inc. Thermoreversible polymers for delivery and retention of osteoinductive proteins
US6878166B2 (en) * 2000-08-28 2005-04-12 Ron Clark Method and implant for securing ligament replacement into the knee
US20030082233A1 (en) * 2000-12-01 2003-05-01 Lyons Karen M. Method and composition for modulating bone growth
US20020114795A1 (en) * 2000-12-22 2002-08-22 Thorne Kevin J. Composition and process for bone growth and repair
EP1399023B1 (en) 2001-06-01 2008-04-30 Wyeth COMPOSITIONS FOR SYSTEMIC ADMINISTRATION OF SEQUENCES ENCODING BONE MORPHOGENETIC PROTEINS& x9;
TWI267378B (en) 2001-06-08 2006-12-01 Wyeth Corp Calcium phosphate delivery vehicles for osteoinductive proteins
EP1448246B2 (en) 2001-11-19 2015-09-09 Scil Technology GmbH Method for producing a homogeneously coated device having osteoinductive and osteoconductive properties
WO2003066000A2 (en) * 2002-02-08 2003-08-14 Wyeth Formulation comprising bioactive agents and method of using same
CA2486113A1 (en) * 2002-05-17 2003-12-04 Wyeth Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins
US7622562B2 (en) * 2002-06-26 2009-11-24 Zimmer Orthobiologics, Inc. Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue
AU2003253049A1 (en) * 2002-09-10 2004-04-30 Scil Technology Gmbh Metal implant coated under reduced oxygen concentration with osteoinductive protein
CN1878565B (zh) 2003-09-12 2011-01-12 惠氏公司 用于递送成骨蛋白的注射型磷酸钙固体小棒剂和糊剂
US7896917B2 (en) * 2003-10-15 2011-03-01 Biomet Sports Medicine, Llc Method and apparatus for graft fixation
EP1729675A4 (en) * 2004-03-05 2011-05-18 Univ Columbia MULTI-PHASE BIODEGRADABLE AND EAST-INTEGRATIVE COMPOSITE SCULPTURE FOR THE BIOLOGICAL FIXATION OF SKELETAL MOLECULAR WEAVE ON BONE
US8002778B1 (en) 2004-06-28 2011-08-23 Biomet Sports Medicine, Llc Crosspin and method for inserting the same during soft ligament repair
WO2006081379A1 (en) * 2005-01-26 2006-08-03 Wyeth Use of sfrps as markers of bmp activity
US20060239951A1 (en) * 2005-03-30 2006-10-26 Alexandre Valentin Methods for stimulating hair growth by administering BMPs
US20060286289A1 (en) * 2005-06-15 2006-12-21 Rita Prajapati Method of intraoperative coating therapeutic agents onto sutures
US20060287675A1 (en) * 2005-06-15 2006-12-21 Prajapati Rita T Method of intra-operative coating therapeutic agents onto sutures composite sutures and methods of use
US20060287676A1 (en) * 2005-06-15 2006-12-21 Rita Prajapati Method of intra-operative coating therapeutic agents onto sutures, composite sutures and methods of use
US20100047309A1 (en) * 2006-12-06 2010-02-25 Lu Helen H Graft collar and scaffold apparatuses for musculoskeletal tissue engineering and related methods
AU2007234612B2 (en) * 2006-12-14 2013-06-27 Johnson & Johnson Regenerative Therapeutics, Llc Protein stabilization formulations
US7718616B2 (en) 2006-12-21 2010-05-18 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US8753391B2 (en) * 2007-02-12 2014-06-17 The Trustees Of Columbia University In The City Of New York Fully synthetic implantable multi-phased scaffold
US8147546B2 (en) * 2007-03-13 2012-04-03 Biomet Sports Medicine, Llc Method and apparatus for graft fixation
US8075562B2 (en) * 2007-06-25 2011-12-13 Wisconsin Alumni Research Foundation Controlled release of biopharmaceutical growth factors from hydroxyapatite coating on bioresorbable interference screws used in cruciate ligament reconstruction surgery
US7678764B2 (en) 2007-06-29 2010-03-16 Johnson & Johnson Regenerative Therapeutics, Llc Protein formulations for use at elevated temperatures
CA2695697A1 (en) 2007-08-07 2009-02-12 Advanced Technologies And Regenerative Medicine, Llc Protein formulations comprising gdf-5 in aqueous acidic solution
BRPI0911048A2 (pt) * 2008-04-14 2015-12-29 Atrm Llc formulações líquidas tamponadas de gdf-5
EP2598177B1 (en) 2010-07-30 2015-06-17 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka mbH Drug delivery devices and growth factor formulations for accelerated wound healing
EP2640429B1 (en) 2010-11-15 2016-12-21 Zimmer Orthobiologics, Inc. Bone void fillers
EP2537538A1 (en) 2011-06-22 2012-12-26 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka mbH Bioresorbable Wound Dressing
WO2014169249A1 (en) 2013-04-12 2014-10-16 The Trustees Of Columbia University In The City Of New York Methods for host cell homing and dental pulp regeneration
JP2017525675A (ja) * 2014-07-09 2017-09-07 メイヨ・ファウンデーション・フォー・メディカル・エデュケーション・アンド・リサーチ 回旋筋腱板異常の処置
EP3322481A4 (en) 2015-07-16 2019-03-06 Mayo Foundation for Medical Education and Research TREATMENT OF ROTATOR COIL DRESSES
CN110893250B (zh) * 2019-10-11 2022-03-15 许和平 瘢痕/粘连阻挡膜及其制备方法和用途
US12310928B2 (en) 2020-11-16 2025-05-27 University Of Utah Research Foundation Enthesis healing

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4877864A (en) 1987-03-26 1989-10-31 Genetics Institute, Inc. Osteoinductive factors
US5013649A (en) 1986-07-01 1991-05-07 Genetics Institute, Inc. DNA sequences encoding osteoinductive products
US5024841A (en) 1988-06-30 1991-06-18 Collagen Corporation Collagen wound healing matrices and process for their production
WO1991018098A1 (en) 1990-05-16 1991-11-28 Genetics Institute, Inc. Bone and cartilage inductive proteins
US5106748A (en) 1986-07-01 1992-04-21 Genetics Institute, Inc. Dna sequences encoding 5 proteins
US5108922A (en) 1986-07-01 1992-04-28 Genetics Institute, Inc. DNA sequences encoding BMP-1 products
WO1992009697A1 (en) * 1990-11-30 1992-06-11 Celtrix Laboratories, Inc. USE OF A BONE MORPHOGENETIC PROTEIN IN SYNERGISTIC COMBINATION WITH TGF-β FOR BONE REPAIR
US5141905A (en) 1986-07-01 1992-08-25 Rosen Vicki A Dna sequences encoding bmp-7 proteins
US5171579A (en) 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
WO1993000050A1 (en) 1991-06-21 1993-01-07 Genetics Institute, Inc. Pharmaceutical formulations of osteogenic proteins
WO1993000432A1 (en) 1991-06-25 1993-01-07 Genetics Institute, Inc. Bmp-9 compositions
US5187076A (en) 1986-07-01 1993-02-16 Genetics Institute, Inc. DNA sequences encoding BMP-6 proteins
US5206028A (en) 1991-02-11 1993-04-27 Li Shu Tung Dense collagen membrane matrices for medical uses
WO1993009229A1 (en) 1991-11-04 1993-05-13 Genetics Institute, Inc. Recombinant bone morphogenetic protein heterodimers, compositions and methods of use
WO1993016099A2 (en) 1992-02-12 1993-08-19 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka Mbh Dna sequences encoding novel growth/differentiation factors
US5256418A (en) 1990-04-06 1993-10-26 Organogenesis, Inc. Collagen constructs
WO1994006399A1 (en) * 1992-09-15 1994-03-31 Creative Biomolecules, Inc. Morphogen-induced periodontal tissue regeneration
WO1994015966A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-9
WO1994015949A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-5
WO1994015965A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-3
WO1994021681A1 (en) 1993-03-19 1994-09-29 Johns Hopkins University School Of Medicine Growth differentiation factor-8
WO1994026892A1 (en) 1993-05-12 1994-11-24 Genetics Institute, Inc. Bmp-11 compositions
WO1994026893A1 (en) 1993-05-12 1994-11-24 Genetics Institute, Inc. Bmp-10 compositions
WO1995001801A1 (en) 1993-07-09 1995-01-19 The Johns Hopkins University School Of Medicine Growth differentiation factor-6
WO1995001802A1 (en) 1993-07-09 1995-01-19 The Johns Hopkins University School Of Medicine Growth differentiation factor-7
WO1995016035A2 (en) * 1993-12-07 1995-06-15 Genetics Institute, Inc. Bmp-12, bmp-13 and tendon-inducing compositions thereof
WO1995033502A1 (en) * 1994-06-03 1995-12-14 Creative Biomolecules, Inc. Manufacture of autogenous replacement body parts
WO1996036710A1 (en) * 1995-05-18 1996-11-21 Genetics Institute, Inc. Bmp-15 compositions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL83003A (en) * 1986-07-01 1995-07-31 Genetics Inst Osteoinductive factors
FR2706749B1 (fr) 1993-06-23 1995-08-25 Oreal Brosse pour appliquer un produit de maquillage, en particulier du mascara

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5187076A (en) 1986-07-01 1993-02-16 Genetics Institute, Inc. DNA sequences encoding BMP-6 proteins
US5013649A (en) 1986-07-01 1991-05-07 Genetics Institute, Inc. DNA sequences encoding osteoinductive products
US5106748A (en) 1986-07-01 1992-04-21 Genetics Institute, Inc. Dna sequences encoding 5 proteins
US5108922A (en) 1986-07-01 1992-04-28 Genetics Institute, Inc. DNA sequences encoding BMP-1 products
US5116738A (en) 1986-07-01 1992-05-26 Genetics Institute, Inc. DNA sequences encoding
US5141905A (en) 1986-07-01 1992-08-25 Rosen Vicki A Dna sequences encoding bmp-7 proteins
US4877864A (en) 1987-03-26 1989-10-31 Genetics Institute, Inc. Osteoinductive factors
US5024841A (en) 1988-06-30 1991-06-18 Collagen Corporation Collagen wound healing matrices and process for their production
US5256418A (en) 1990-04-06 1993-10-26 Organogenesis, Inc. Collagen constructs
WO1991018098A1 (en) 1990-05-16 1991-11-28 Genetics Institute, Inc. Bone and cartilage inductive proteins
WO1992009697A1 (en) * 1990-11-30 1992-06-11 Celtrix Laboratories, Inc. USE OF A BONE MORPHOGENETIC PROTEIN IN SYNERGISTIC COMBINATION WITH TGF-β FOR BONE REPAIR
US5206028A (en) 1991-02-11 1993-04-27 Li Shu Tung Dense collagen membrane matrices for medical uses
WO1993000050A1 (en) 1991-06-21 1993-01-07 Genetics Institute, Inc. Pharmaceutical formulations of osteogenic proteins
WO1993000432A1 (en) 1991-06-25 1993-01-07 Genetics Institute, Inc. Bmp-9 compositions
WO1993006872A1 (en) * 1991-10-11 1993-04-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
US5171579A (en) 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
WO1993009229A1 (en) 1991-11-04 1993-05-13 Genetics Institute, Inc. Recombinant bone morphogenetic protein heterodimers, compositions and methods of use
WO1993016099A2 (en) 1992-02-12 1993-08-19 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka Mbh Dna sequences encoding novel growth/differentiation factors
WO1994006399A1 (en) * 1992-09-15 1994-03-31 Creative Biomolecules, Inc. Morphogen-induced periodontal tissue regeneration
WO1994015949A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-5
WO1994015966A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-9
WO1994015965A1 (en) 1993-01-12 1994-07-21 Johns Hopkins University School Of Medicine Growth differentiation factor-3
WO1994021681A1 (en) 1993-03-19 1994-09-29 Johns Hopkins University School Of Medicine Growth differentiation factor-8
WO1994026892A1 (en) 1993-05-12 1994-11-24 Genetics Institute, Inc. Bmp-11 compositions
WO1994026893A1 (en) 1993-05-12 1994-11-24 Genetics Institute, Inc. Bmp-10 compositions
WO1995001801A1 (en) 1993-07-09 1995-01-19 The Johns Hopkins University School Of Medicine Growth differentiation factor-6
WO1995001802A1 (en) 1993-07-09 1995-01-19 The Johns Hopkins University School Of Medicine Growth differentiation factor-7
WO1995016035A2 (en) * 1993-12-07 1995-06-15 Genetics Institute, Inc. Bmp-12, bmp-13 and tendon-inducing compositions thereof
WO1995033502A1 (en) * 1994-06-03 1995-12-14 Creative Biomolecules, Inc. Manufacture of autogenous replacement body parts
WO1996036710A1 (en) * 1995-05-18 1996-11-21 Genetics Institute, Inc. Bmp-15 compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
RODEO ET AL., BONE AND JOINT SURGERY, vol. 75-A, 1993, pages 1795 - 1803
RODEO S A ET AL: "Bone morphogenetic protein enhances early tendon healing in a bone tunnel", ORTHOPAEDIC RESEARCH SOCIETY, 41ST ANNUAL MEETING, 13 February 1995 (1995-02-13) - 16 February 1995 (1995-02-16), Orlando, Florida, p. 288, XP009140978 *
RODEO S A ET AL: "Tendon-healing in a bone tunnel. A biomechanical and histological study in the dog", THE JOURNAL OF BONE AND JOINT SURGERY, vol. 75-A, no. 12, December 1993 (1993-12-01), pages 1795 - 1803, XP002609283, ISSN: 0021-9355 *

Also Published As

Publication number Publication date
KR19990014932A (ko) 1999-02-25
CA2220555C (en) 2011-07-19
US6187742B1 (en) 2001-02-13
HK1017841A1 (en) 1999-12-03
CA2220555A1 (en) 1996-12-12
DE69629294T2 (de) 2004-04-29
ES2203701T3 (es) 2004-04-16
EP1364656A2 (en) 2003-11-26
JPH11507032A (ja) 1999-06-22
CN1133462C (zh) 2004-01-07
WO1996039169A1 (en) 1996-12-12
DK1364656T3 (da) 2013-12-16
EP0831884A1 (en) 1998-04-01
HU222664B1 (hu) 2003-09-29
AU5923496A (en) 1996-12-24
PT831884E (pt) 2003-11-28
HUP9802556A3 (en) 1999-04-28
EP0831884B1 (en) 2003-07-30
CN1186438A (zh) 1998-07-01
ES2440441T3 (es) 2014-01-29
HUP9802556A1 (hu) 1999-03-29
FI974395A0 (fi) 1997-12-02
KR100440645B1 (ko) 2004-09-18
OA10547A (en) 2002-05-31
TW449478B (en) 2001-08-11
ATE245996T1 (de) 2003-08-15
FI116511B (fi) 2005-12-15
EP1364656B1 (en) 2013-11-20
EP1364656A3 (en) 2003-12-10
AU699918B2 (en) 1998-12-17
DE69629294D1 (de) 2003-09-04
DK0831884T3 (da) 2003-11-03
FI974395L (fi) 1997-12-02

Similar Documents

Publication Publication Date Title
US6187742B1 (en) Method for healing and repair of connective tissue attachment
US7842669B2 (en) Methods and compositions for healing and repair of articular cartilage
EP1148897B1 (en) Methods and compositions for healing and repair of articular cartilage
KR100704537B1 (ko) 관절 연골의 치유 및 회복을 위한 조성물
HK1017841B (en) Methods and compositions for healing and repair of connective tissue attachment
FI20055480A7 (fi) BMP-4-, BMP-12-, BMP-13-ja MP-52-polypeptidien käyttö valmistettaessa sidekudoskiinnityksen regenerointiin tarkoitettuja farmaseuttisia koostumuksia
MXPA01007731A (en) Methods and compositions for healing and repair of articular cartilage

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AC Divisional application: reference to earlier application

Ref document number: 1364656

Country of ref document: EP

Kind code of ref document: P

Ref document number: 0831884

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110903